Steroid carbamates

ABSTRACT

CARBAMIC ACID ESTERS OF 3B-HYDROXY-$4 OR $5-STEROIDS, WHICH CAN BE OPTIONALLY SUBSTITUTED WITH CHLORINE IN THE 4 AND/OR 6-POSITIONS AND WHICH ARE USEFUL AS PROGESTATIONAL, ANDROGENIC, ANABOLIC, ANTIESTROGENIC AND/OR ANTIGONADOTROPIC AGENTS, AND A PROCESS FOR PREPARING THESE CARBAMIC ACID ESTERS.

U i d States Patent 0,

3,787,453 STEROID CARBAMATES Kenneth Earl Fahrenholtz, Bloomfield, N.J.,assignor to Hotfmann-La Roche Inc., Nutley, NJ. No Drawing. Filed Oct.26, 1971, Ser. No. 192,306 Int. Cl. C07c 169/20 US. Cl. 260-3974 19Claims ABSTRACT OF THE DISCLOSURE Carbamic acid esters of 3B-hydroxy-Aor A -steroids, which can be optionally substituted with chlorine in the4 and/or 6-positions and which are useful as progestational, androgenic,anabolic, antiestrogenic and/or antigonadotropic agents, and a processfor preparing these carbamic acid esters.

SUMMARY OF THE INVENTION In accordance with this invention, it has beenfound that a compound selected from the group consisting of compounds ofthe formulas:

and

wherein X and X are halogen or hydrogen; R and R are hydrogen, loweralkyl, lower alkenyl or aryl; R

is hydrogen, lower alkyl or lower alkylidene; R is individuallyhydrogen, lower alkyl, hydroxy or lower alkanoyloxy; R is individuallyhydroxy, acetyl, lower alkanoyloxy or -O-%NH:

or R and R taken together form an oxo group; and the dotted bond is asingle bond or a double bond between the carbon atoms in the 6 and 7position; with the proviso that when R is acetyl, R is hydroxy or loweralkanoyloxy and when R is -O(3NH2 hydroxy or lower alkanoyloxy, R ishydrogen or lower alkyl; and with the further proviso that when X and Xare hydrogen, the dotted bond is a single bond;

exhibit endocrine activity. All compounds of Formulas I and II wherein Ris hydroxy, lower alkanoyloxy or Oi J-NH2 exhibit androgenic and/oranabolic activity and antigonadotropic activity. All compounds ofFormulas I and Patented Jan. 22, 1974 II wherein 'R is acetyl exhibitprogestational activity and anti-estrogenic activity.

DETAILED DESCRIPTION OF THE INVENTION As used throughout thisapplication, the term lower alkyl comprehends straight chain andbranched chain saturated hydrocarbon groups having from one to sixcarbon atoms, such as methyl, ethyl and isopropyl. Similarly, as usedherein, the term lower alkenyl comprehends olefinically unsaturatedhydrocarbons having from 2 to 6 carbon atoms such as vinyl, allyl,propenyl and butenyl. As also used herein, the term lower alkanoyloxycomprehends acyloxy groups having 1 to 6 carbon atoms such as formyloxy,acetyloxy and propionyloxy. As still further used herein, the termhalogen includes fluorine, chlorine, bromine and iodine unless otherwisestated, with chlorine being preferred. As further used herein, the termlower alkoxy comprehends lower alkyloxy groups having 1 to 6 carbonatoms such as methoxy, ethoxy and propoxy. As still further used herein,the term aryl comprehends mono-nuclear aromatic hydrocarbons such asphenyl, tolyl, etc., preferably phenyl, which can also be unsubstitutedor substituted in one or more positions with a nitro, halo, lower alkylor lower alkoxy substituent, wherein lower alkyl, halo and lower alkoxyare as defined above. .As still further used herein, the term loweralkylidene comprehends lower alkylidene groups having from 1 to 6 carbonatoms such as methylene, ethylidene and propylidene.

In accordance with this invention, among the preferred compounds ofFormula I are the pregnane compounds of the formula:

1 (Lo R1 wherein R R [R and R, are as above.

Among the compounds of Formula Ia, the particularly preferred compoundsof Formula I include compounds wherein the l'6e-substituent [R ishydrogen.

In accordance with this invention, also among the preferred compounds ofFormula I are the pregnane com pounds of the formula:

wherein X R R R and R are as above.

Among the compounds of Formula Ib, the particularly preferred compoundsof Formula I include the compounds of the formula:

wherein R R R and R are as above and X' is hydro gen or chlorine.

In accordance with this invention, further among the preferred compoundsof Formula I are the androstane compounds of the formula:

wherein R R R and R are as above; and R' is individually hydroxy orlower alkanoyloxy or R and R' taken together form an oxo group.

Among these compounds of Formula Id, the particularly preferredcompounds of Formula I include compounds wherein the IGe-substituent Ris hydrogen.

In accordance with this invention, among the preferred compounds ofFormula II are the androstane compounds of the formula:

wherein R R R and R' are as above.

Among these compounds of Formula IIa, the particularly preferredcompounds of Formula II include compounds wherein the l7a-substituent Ris hydrogen or methyl.

One method for obtaining the compounds of Formula I or II is by reactinga compound selected from the group consisting of compounds of theformulas:

and

(IIIb) wherein X X R R R and the dotted bond are as above;

with a compound of the formula:

R: (IV) wherein R and R are as above.

Another method for obtaining a compound of Formula I or II wherein R ishydrogen is by reacting a compound selected from the group consisting ofcompounds of the wherein X X R R R and the dotted bond are as above;

with a compound of the formula:

wherein R is as above.

Still another method for obtaining a compound of Formula I or II whereinR and R are hydrogen and/or wherein R is is by reacting a compoundselected from the group consisting of compounds of the formulas:

and

(VIIb) wherein R is hydroxy or 5Q, X R R R R R and the dotted bond areas above; and at least one of R and R is hydroxy;

with sodium cyanate and trifluoroacetic acid.

The reaction of the compounds of Formula IIIa or HIb with an amine ofFormula IV can be suitably carried out in the presence of an inertorganic solvent. Any conventional inert organic solvent such as diethylether or tetrahydrofuran can be utilized in this reaction. If desired,an excess of the liquid amine of Formula IV can also be suitablyutilized as the solvent medium for the reaction. In carrying out thisreaction, temperature and pressure are not critical, and in general,this reaction can be carried out at room temperature (25 C.) and atatmospheric pressure. In carrying out this reaction, temperatures higheror lower than room temperature can also be utilized, with the refluxtemperature of the reaction mixture being preferred.

The reaction of the compounds of Formula Va or Vb with an isocyanate ofFormula VI can be suitably carried out in the presence of a catalyticquantity of an organic amine base. In carrying out this reaction, anyconventional organic amine base can be utilized, with pyridine,n'iethylamine and collidine being preferred. The reaction can also besuitably carried out in the presence of an inert organic solvent. Anyconventional inert organic solvent may be utilized in this reaction suchas benzene, diethyl ether or tetrahydrofuran. -In carrying out thisreaction, temperature and pressure are not critical, and in general,this reaction can be carried out at room temperature and at atmosphericpressure. In carrying out this reaction, temperatures higher or lowerthan room temperature can also be utilized.

The reaction of the compounds of Formula VIIa or VIIb with sodiumcyanate and trifluoracetic acid can be suitably carried out in thepresence of an inert organic solvent. Any conventional inert organicsolvent such as dichloromethane and tetrahydrofuran, can be utilized inthis reaction. In carrying out this reaction, temperature and pressureare not critical and, in general, this reaction can be carried out atroom temperature and at atmospheric pressure. In carrying out thisreaction, temperatures of 0 C. to 30 C. are preferred, with 20 C. beingparticularly preferred.

The compounds of Formula IIIa or IIIb can be suitably obtained from thereaction of a compound of Formula Va or Vb with phenyl chloroformate.This reaction is preferably carried out in the presence of an organicamine which will react with and remove the HCl produced during the mainreaction. In this reaction, any conventional organic amine base can beutilized, with pyridine, triethylamine and collidine being preferred.This reaction can also be carried out in the presence of an inertorganic solvent. In this reaction, any conventional inert organicsolvent may be utilized, with the aforementioned organic amine basesbeing preferred. In carrying out this reaction, temperature and pressureare not critical, and in general, the reaction can be suitably carriedout at room temperature and atmospheric pres- (VIIIa) and wherein X X RR R and the dotted bond are as above.

The compounds of Formula VIIIa or VIIIb can be suitably reduced to thecompounds of Formula Va or Vb by treatment with a reducing agent whichselectively reacts with the 3-oxo substituent. In this reaction, anyconventional, selective, 3-oxo reducing agent can be utilized withlithium tri-t-butoxyaluminum hydride being preferred. This reductionreaction can be suitably carried out in the presence of an inert organicsolvent. In this reaction, any conventional inert organic solvent can beutilized, with diethyl ether and tetrahydrofuran being preferred. Inthis reaction, temperature and pressure are not critical, and ingeneral, the reaction can be suitably carried out at room temperatureand atmospheric pressure. In this reaction, temperatures higher or lowerthan room temperature can be utilized, with the reflux temperature ofthe reaction mixture being preferred.

The compounds of this invention, as well as the intermediates which areuseful for their preparation, are characterized by endocrinologicalutility. Thus, the compounds of Formulas I and II, as well as Illa andH11), can be administered internally, for example, orally orparenterally, with dosage adjusted to individual requirements, in theform of conventional pharmaceutical preparations. For example, thecompounds of Formula I or H can be administered in conventionalpharmaceutical solid or liquid forms, such as tablets, pills, capsules,solutions, suspensions, emulsions, or the like. These pharmaceuticalpreparations can contain the compounds of this invention as an activeingredient in concentrations of about 0.01% to 99% by weight. Thesepharmaceutical preparations can also contain conventional pharmaceuticalcarriers and excipients, such as water, talc, corn starch, polyalkyleneglycols, emulsifying agents, buffering agents, agents for the adjustmentof osmotic pressure, Vaseline and/ or the like. Though it is preferredto administer the endocrinologically useful compounds of this inventioninternally, the progestationally useful compounds of Formulas I and IIabove can be administered topically. For this purpose, i.e., topicaladministration, these compounds can be administered in conventionaltopical administration forms, such as ointments or creams, incombination with conventional topical carriers such as petrolatum,stearic acid or the like. Also compositions containing an activeingredient of this invention can be subjected to conventionalpharmaceutical processes such as sterilization or the like. Also, thepharmaceutical compositions of this invention can contain other activeingredients. Moreover, these endocrinologically active compounds can beadministered as feed additives, and for this purpose can be admixed withconventional animal feeds or conventional animal premixes. Though asindicated, dosages of the endocrinologically useful compounds of thisinvention should be adjusted to individual needs, the compounds of thisinvention can be administered internally in daily dosage regimens offrom about 0.005 mg./kg. to about 0.15 mg./kg. per day. These dosagescan be administered in unit or divided dosage forms.

The pregnane compounds of this invention exhibit useful progestationalactivity as indicated in animals. For example, the progestationalcompounds of this invention, when administered to estrogen primedimmature female rabbits for five days show the presence ofprogestational activity by a secretory type endometrial responseobserved on histological sections prepared from the rabbits uteri andexamined microscopically. The following compounds, when administered inthe manner set forth above, showed progestational activity atsubcutaneous dosages of less than ,ugJday:

6-chloro-3,3,17a-dihydroxypregna-4,6-dien-20-one 3-carbamate 17-acetate;

6-chloro-3fi,17a-dihydroxypregna-4,6-dien-20-one S-dimethylcarbamate17-acetate;

fi-chloro-Sfi,17e-dihydroxypregna-4,fi-dien-ZO-one 3-ethylcarbamate17-acetate; and

4,6-dichloro-3B,l7m-dihydroxypregna-4,6-dien-20-one 3-carbamate17-acetate.

The androstane compounds of this invention exhibit useful androgenicand/or anabolic activity. For example, the androgenic and/or anabolicactivity of compounds of this invention is shown in a procedure whereinfive castrated rats weighing approximately 40-50 g. each are giveneither oral dosages or subcutaneous injections of the compound suspendedin sesame oil, whereas a control group of five rats is administered thesesame oil vehicle only. After seven days of treatment all animals areautopsied and weights of their ventral prostates and levator ani musclesare determined. The weight of their levator ani as compared to thecontrol group of rats is the criterion used for determining anabolicactivity. The weight of their ventral prostates as compared to thecontrol group of rats is the criterion used for determining androgenicactivity. The following compounds, when administered in the manner setforth above, showed androgenic and/or anabolic activity at dosages of1.0 rug/day per os:

17a-methylandrost-4-ene-3,8,17,6-diol B-ethylcarbamate;17a-methylandrost-4-ene-3B, 17,8-diol 3-methylcarbamate;17a-methylandrost-4-ene-3/3,l7 3-diol 3-allylcarbamate;17a-methylandrost-4-ene-3B,l7,8-diol 3-butylcarbamate;androst-4-ene-3B,17fi-diol 3-ethylcarbamate 17-acetate;lTa-methylandrost-S-ene-Bfi,l7fi-diol 3-phenylcarbamate;17a-methylandrost-S-cue-3,8,17,6-diol bis-carbamate; andandrost-5-ene-3,8,l7fi-diol 3-ethylcarbamate l7-acetate.

The pregnane compounds of this invention also exhibit usefulanti-estrogenic activity as indicated in animals. For example, theanti-estrogenic activity of the compounds of this invention is shown ina procedure wherein groups of ten immature female rats are given once aday, for three days, an oral dose of the compound concurrently with asubcutaneous injection of 0.1 g. of estradiol in sesame oil. 0n thefourth day, the uteri are removed at autopsy and weighed. The weights ofthe uteri compared to those of a control group of rats is the criterionused for determining anti-estrogenic activity. The following compounds,when administered subcutaneously in the manner set forth above, showedantiestrogenic activity at dosages of 500 ,ug./ day:

6-chloro-3 13,l7a-dihydroxypregna-4,6-dien-20-one B-carbamate17-acetate;

8 6-chloro-35,17a-dihydroxypregna-4,6-dien-20-one S-dimethylcarbamate17-acetate; 6-chloro-3,8,17a-dihydroxypregna-4,6-dien-20-one3-ethylcarbamate 17-acetate; and 4,6-dichloro-3 ,3,17a-dihydroxypregna-4,6-dien-20-one S-carbamate 17-acetate.

The androstane compounds of this invention exhibit usefulantigonadotropic activity as indicated in animals. For example, theantigonadotropic activity of the compounds of this invention is shown ina procedure wherein the compounds are administered for ten days toimmature male rats. At autopsy, the testes, seminal vesicles and ventralprostates are removed and then respective Weights determined. Theweights of these organs as compared with the control groups of rats isthe criterion used for determining the antigonadotropic activity. Thefollowing compounds, when administered in the manner set forth above,showed antigonadotropic activity at dosages of 1.0 mg./day per os:

17u-methylandrost-4-ene-3fl,17,8-diol 3-ethylcarbamate;

17a-methylandrost-4-ene-3fi,l7fi-diol 3-methylcarbamate;

17a-methylandrost-4-ene-3fl,17,3-diol 3-allylcarbamate;

androst-4-ene-3 8,17,8-diol 3-ethylcarbarnate 17-acetate;

and

17a-methylandrost-5-ene-3p,17fi-diol 3-ethylcarbamate.

The examples which follow illustrate the invention. All temperatures arein degrees centigrade.

EXAMPLE 1 3,6,17a-dihydroxypregn-4-en-20-one-3-carbamate- 17-acetate Toa solution of 3.74 g. (0.01 mole) of 3B,l7a-di-hydroxypregn-4-en-20-one17-acetate in 5 ml. of dry pyridine was added 2.5 ml. of phenylchloroformate. A gummy precipitate soon formed and after an additional10 ml. of pyridine was added the precipitate gradually solidified. Thesolid was broken up and the slurry was stirred at room temperature fornine days. The reaction was then poured with stirring into 600 ml. ofice and water. The resulting 3,8,17a-dihydroxypregn-4-en-20-one3-phenylcar-bonate 17-acetate precipitate was collected by filtration,washed with water and dissolved in a mixture of diethyl ether andtetrahydrofuran. The organic layer was dried and concentrated to a finalvolume of 75 ml. Fifteen milliliters of this solution (corresponding to750 mg. of the pregnane starting material) was added dropwise to 15 ml.of liquid ammonia (-33 C.) and the resulting solution was allowed toreflux for 3.5 hr. The ammonia was allowed to evaporate overnight andthe residual solution was poured into 500 ml. of ice and water. Theresulting gummy precipitate was collected by filtration and dissolved indichloromethane. The solution was dried and concentrated and the residuewas recrystallized several times from diethyl ether-hexane to give 38,170- dihydroXypregn-4-en-20-one 3-carbamate l7-acetate as colorlesscrystals; melting point (M.P.) 216 (dec.).

EXAMPLE 2 G-chloro-3p,17a-dihydroxypregna-4,6-dien 20 one 3- carbamate17-acetate To a vigorously stirred solution of 1.23 g. (3.0 mmoles) of6-chloro-3B,17a-dihydroxypregna-4,6-diene-20-one 17- acetate in 37 ml.of pyridine at room temperature was added 1.05 ml. of phenylchloroformate. After stirring for 2 hrs. the reaction mixture was pouredinto 1 l. of ice and water. The resulting 6 chloro313,17-ot-dihydroxypregna-4,6-dien-20-one 3-phenylcarbonate 17-acetateprecipitate was collected by filtration and dissolved in diethyl ether.The solution dried and concentrated and the phenylcarbonate residue wasdissolved in 50 ml. of tetrahydrofuran. One half of this solution wasadded dropwise to 25 ml. of liquid ammonia at reflux temperature andafter stirring for 1.5 hrs. the excess ammonia was allowed to evaporate.The residue was poured into 1 l. of ice and water. The resultingprecipitate was collected by filtration and dissolved in diethyl ether,and this solution was then dried and concentrated. The resulting yellowoil was crystallized and recrystallized from methanol to give 6-chloro-3fl,l7-u-dihydroxypregna 4,6 dien 20 one 3- carbamate 17-acetateas colorless crystals; M.P. 2l3215 (dec.).

EXAMPLE 3 6-chloro-3fl,17a-dihydroxypregna-4,6-dien-20-one 3-dimethylcarbamate 17-acetate tallized from dichloromethane.-methanol togive 6-chloro- 3,B,17a-dihydroxypregna 4,6 dien-20-one 3dimethylcat-bamate 17-acetate as colorless crystals; M.P. 243-244"(dec.).

EXAMPLE 4 6-chloro-3fi,l7a-dihydroxypregna-4,6-dien-ZO-one 3-ethylcarbamate 17-acetate To a solution of 0.30 g. (0.74 mmole) of6-chloro-3p, 17a-dihydroxypregna-4,6-dien-20-one 17-acetate in 15 ml. ofbenzene, containing three drops of pyridine, was added in severalportions over 8 days, 16.5 ml. of ethyl iso cyanate. The solution wasstirred for an additional 6 days and then shaken with 300 ml. of ice andwater. The aque ous layer was extracted three times with diethyl etherand the combined organic layers were washed with water, dried andconcentrated. The residue was crystallized from diethyl ether-hexane andrecrystallized from methanolwater to give6-chloro-3B,17u-dihydroxypregna-4,6-dien- 20-one 3-ethylcarbamate17-acetate as colorless crystals; M.P. 220-221 (dec.).

EXAMPLE 5 4,6-dichloro-3B, 17a-dihydroxypregna-4,6-dien-20-one3-carbamate 17-acetate To a vigorously stirred solution of 0.50 g. (1.13mmoles) of 4,6-dichloro 318,170: dihydroxypregna-4,6- dien-20-one17-acetate in 15 ml. of pyridine at room temperature was added 0.28 ml.of phenyl chloroformate. The reaction was stirred overnight, anadditional 0.14 ml. of phenyl chloroformate was added and the reactionwas stirred overnight again. It was then poured into 450 ml. of ice andwater. The resulting 4,6-dichloro-35,17a-dihydroxypregna-4,6-dien-20-one3-phenylcarbonate l7-acetate precipitate was collected by filtration anddissolved in 30 ml. of tetrahydrofuran. The solution was dried andconcentrated at room temperature to 15 ml. This phenylcarbonate solutionwas then added dropwise to 15 ml. of refluxing ammonia. The reaction wasstirred and allowed to reflux for 2 /2 hrs. and then the ammonia waspoured into 500 m1. of ice and water and the resulting precipitate wascollected by filtration and dissolved in dichloromethane. The solutionwas dried and concentrated. The residue was crystallized from methanolto give 4,6-dichloro3fl, 17u-dihydroxypregna-4,6 dien 20-one 3-carbamatel7- acetate as colorless crystals; M.P. 265-267 (dec.).

EXAMPLE 6 4,6-dichloro-3fl,l7a-dihydroxy-l6-methylenepregna-4,6-dien-20-one S-dimethylcarbamate l7-acetate To a solution of 0.500 g.(1.10 mmoles) of 4,6-dichloro-3p,17a-dihydroxy 16methylenepregna-4,6-dien- 20-one 17-acetate in 15 ml. of pyridine wasadded 0.81 ml. of phenyl chloroformate. A precipitate formed immediatelywhich was initially gummy but which soon was crystalline. After thereaction had been stirred at ambient temperature for 1.5 hrs., it waspoured into 200 ml. of ice and water. The resulting 4,6-dichloro 313,17adihydroxy-l6-methylenepregna-4,6-dien 20 one 3 phenylcarbonate17-acetate precipitate was collected by filtration and dissolved indichloromethane. The solution was dried and concentrated to give aresidue containing the crude phenylcarbonate. This was dissolved in 20ml. of tetrahydrofuran and added dropwise to 20 ml. of diethylaminecooled in a Dry Ice bath. The reaction was then stirred at roomtemperature under a Dry Ice condenser for 3 hrs. The excessdimethylamine was allowed to evaporate overnight and the remainingsolvent was removed under vacuum. The residue was dissolved in benzene,and the solution was washed with 1 N hydrochloric acid and with water,dried, and evaporated to a yellow oil. This was oiled out of diethylether-hexane several times and finally crystallized. Recrystallizationfrom diethyl etherhexane gave 4,6-dichloro-3fi,l7a-dihydroxy 16methylenepregna 4,6 dien-ZO-one 3-dimethylcarbamate l7-ace tate ascolorless crystals; M.P. 162164 C.

EXAMPLE 7 17a-methylandrost-4-ene-3p,17 3-diol 3-ethylcarbamate Amixture of 3.00 g. (0.0098 mole) offlat-methylandrost-4-ene-3/3,17fl-diol, 30 ml. of dry benzene, 2.6 ml.of ethyl isocyanate and 2 drops of pyridine was stirred at 50 for 3days. Another 1.3 ml. of ethyl isocyanate was added and heating wascontinued one more day. The cooled reaction was poured into ice waterand extracted with dichloromethane. The extracts were Washed with water,dried and evaporated. The residue was crystallized from methanol and thesolid product was adsorbed onto a column of silica gel from benzene.Elution with diethyl ether and crystallization fromdichloromethane-hexane galve 17a-methylandrost 4 ene-3 3,17B,diol3-ethylcarbamate as colorless crystals; M.P. 137-1405".

EXAMPLE 8 17u-methylandrost-4-ene-3B-diol 3-ethylcarbamate A solution of5.00 g. (0.0164 mole) of l7a-rnethylandrost-4ene-3B,17/3-diol, 4.5 ml.of ethyl isocyanate and 5 drops of pyridine in 250 ml. oftetrahydrofuran was allowed to stand at room temperature. After 3 weeksabout 15 mg. of sodium methoxide was added and 11 weeks later thereaction was poured into 2.5 l. of ice and water containing 40 ml. ofconcentrated ammonium filtration, washed well with water and dissolvedin dichloromethane. The solution was washed twice with water, dried andconcentrated to a colorless foam. This was crystallized from diethylether-hexane and recrystallized from dichloromethane-hexane to give17a-methylandr0st- 4-ene-3B,l7}8-diol 3-ethylcarbamate as colorlesscrystals; M.P. 137-139".

EXAMPLE 9 17a-methylandrost-4-ene-3 8,17B-diol B-phenylcarbonate To avigorously stirred solution of 15.00 g. (0.049 mole) of17a-methylandrost-4-ene3fi,17fi-diol in 600 ml. of pyridine was addedover 30 min. 17.1 ml. of phenyl chloroformate. The reaction was stirredat room temperature for 2.75 hrs. and then poured into 8 l. of ice andwater. The resulting precipitate was collected by filtration, washedwith water, and dissolved in diethyl ether containing a littledichloromethane. The solution was dried over sodium sulfate andconcentrated to give a colorless oil which was diluted to 250 ml. withtetrahydrofuran to give a stock solution of 17a-methylandrost-4-ene-313,17B-diol 3-phenylcarbonate. Fifty milliliters of this stock solutionwas diluted with 50 ml. of tetrahydrofuran and mixed with 15 ml. ofdiethylamine. After standing at room temperature for 3 days, tlcindicated no reaction had taken place and the phenylcarbonate wasrecovered by pouring the reaction into 500 ml. of ice and water. Theresulting solid was dissolved in diethylether, dried over sodiumsulfate, filtered over a short column of silica gel and concentrated.The residue was recrystallized from diethyl ether-hexane to givel7u-methylandrost-4-ene-3,6, 17/3-diol 3-phenylcarbonate as colorlesscrystals; M.P. 140.5142.5.

EXAMPLE 10 17a-methylandrost-4-ene-3fi,17 3-diol 3-methylcarbamate To asolution of ml. of methylamine in 50 ml. of dioxane cooled to 70 wasadded a solution of the crude 17u-methylandrost-4-ene-3,8,17B-diol3-phenylcarbonate prepared as in Example 9 from 3.00 g. (9.8 mmoles) of17a-methylandrost-4-ene-318,17B-diol in 50 ml.

, of dioxane. The solution was stirred at 70 C. for one hour and then atroom temperature (-25" C.) overnight. Most of the dioxane was removedunder vacuum and the residue was mixed with 250 ml. of ice and water.The resulting oil was isolated by decantation and dissolved indichloromethane. The solution was dried and concentrated under vacuum.The residue was dissolved in hexane and adsorbed onto a silica gelcolumn. Elution with 15% diethyl ether in hexane removed less polarimpurities and elution with diethyl ether gave material rich in product.Recrystallization from diethyl ether-hexane gave 170:-methylandrost-4-ene-3 3,17,8-diol 3 methylcarbamate as colorlesscrystals, M.P. 97-102" C. with resolidification and remelting at155.5-157.5 C.

EXAMPLE 11 17u-methylandrost-4-ene-3p,17f3-diol 3-methylcarbamateTreatment of 17a-methylandrost-4-cue-3,8,17/3-diol with methylisocyanate, according to the procedure of Example 8, gave17u-methylandrost-4-ene-3B,17/3-diol 3-methylcarbamate as colorlesscrystals; M.P. 96-102"; with resolidification and remelting at M.P.154-15 6.

EXAMPLE 12 17oc-methylandrost-4-ene-2fl,17,3-diol 3-allylcarbamateTreatment of 17u-methylandrost-4-ene-3fi,17B-diol with allyl isocyanate,according to the procedure of Example 8, gave after recrystallizationfrom dichloromethane-diethyl ether-hexane17u-methylandrost-4-ene-3,8,17fi-diol 3- allylcarbamate; M.P. 141-142".

EXAMPLE 13 17a-methylandrost-4-ene-3,B,17fl-diol 3-butylcarbamateTreatment of 17u-methylandrost-4-ene-3 8,17,8-diol with butylisocyanate, according to the procedure of Example 8, gave afterrecrystallization from dichloromethane-diethyl ether17a-methylandrost-4-ene-3fl,17B-diol 3-butylcarbamate as colorlesscrystals; M.P. 158-1595 C.

EXAMPLE 14 17a-methylandrost-5-ene-3fi,l7/3-diol bis-carbamate To aslowly stirred slurry of 15.81 g. (0.052 mole) of17a-methylandrost-5-ene-3 8,l7p-diol and 6.75 g. (0.104 mole) of sodiumcyanate in 24 m1. of dichloromethane cooled to was added over one hour8.52 ml. (0.105 mole) of trifluoroacetic acid. The reaction was stirredovernight at room temperature, diluted with dichloro- 12 EXAMPLE 1517a-methylandrost-5-ene-3fi,l7fl-diol 3-ethylcarbamate A solution of10.7 g. (0.035 mole) of 17a-methylandrost-5-ene3 8,17fi-diol and 25 g.(0.35 mole) of ethyl isocyanate in 200 ml. of tetrahydrofuran containing5 drops of pyridine was allowed to stand at room temperature for 41days. It was then poured into 2 l. of ice and water containing 45 ml. ofconcentrated ammonium hydroxide. The resulting precipitate was collectedby filtration and dissolved in dichloromethane. The solution was driedand concentrated to a pale yellow oil which was crystallized fromdiethyl ether-hexane. Recrystallization from dichloromethane-hexane thenfrom methanol-water and finally from dichloromethane-hexane gave17u-methylandrost-5-ene-3p,l7fl-diol 3-ethylcarbamate was colorlesscrystalls; M.P. -172".

EXAMPLE l6 17a-methylandrost-5-ene-3 8,17,Bdiol S-phenylcarbamate Aninitially heterogeneous mixture of 5.00 g. (0.0164 mole) of17a-methylandrost-5-ene-3/3,17 8-diol, 6.5 ml., (7.1 g., 0.059 mole) ofphenyl isocyanate, 50 ml. of benzene, 10 ml. of dioxane and 3 drops ofpyridine were stirred at room temperature for 3 days. The reaction wasthen stirred with 500 ml. of ice and water for 1.5 hours and extractedwith dichloromethane. The solution was dried-and concentrated. Thepartly crystalline residue was triturated with dichloromethane to removesome insoluble diphenylurea and the solution was concentrated with thesimultaneous addition of hexane to give crude crystalline product. Thiswas recrystallized from diethyl ether-hexane to give17u-methylandrost-5-ene-3/9,17fl-dio1 3-phenylcarbamate as colorlesscrystals; M.P. 203.5-

EXAMPLE 17 Androst-4-ene-3fi,17B-diol 3-ethylcarbamate 17-acetate wasadded 4.5 g. of sodium borohydride. After 45 min.

another 0.45 g. of sodium borohydride was added and 10 min. later 7.8ml. of acetic acid was added. After the initial foaming had subsided thereaction mixture was poured into a 2 l. of ice and water. The resultingprecipitate was collected by filtration and dissolved indichloromethane. The solution was dried and concentrated and the residuewas crystallized from dichloromethane-diethyl ether and thenrecrystallized from diethyl ether to givea mixture of alcohols of M.P.149-152, containing androst-4-ene- 36,17B-diol 17-acetate.

A solution of 5.00 g. of the above 149-152 mixture of alcohols, 30 ml.of benzene, 20 ml. of tetrahydrofuran, 3 drops of pyridine and 8.0 ml.of ethyl isocyanate was allowed to stand at room temperature for 18days. The reaction was then stirred with 1 l. of ice and water for onehour and extracted with dichloromethane. The extracts were dried andconcentrated and the residue was recrystallized fromdichloromethane-diethyl ether-hexane to give androst-4-ene-3fl,17,8-diol3-ethylcarbamate 17-acetate as colorless crystals; M.P. 179-181".

EXAMPLE 18 3,B-hydroxyandrost-5-en-17-one ethylcarbamate A solution of12.68 g. (0.044 mole) of 3B-hydroxyandrost -5-en-17-one, 25 g. (0.35mole) of ethyl isocyanate and 5 drops of pyridine in 60 ml. oftetrahydrofuran was stirred at room temperature for 14 days. It was thenpoured into one liter of ice and water containing 42 ml. of'concentrated ammonium hydroxide. The resulting precipitate. wascollected by filtration and dissolved in dichloromethane. The solutionwas Washed twice with water, dried and evaporated to give a colorlesscrystalline residue. Recrystallization from dichloromethane-ethylacetate gave .3 S-hydroxyandrost-5-en-17-one ethylcarbamate; M.P.18l.5183.

EXAMPLE 19 Androst-5-ene-3B,l7B-diol 3-ethylcarbamate To a solution of10.60 g. (0.0295 mole) of 3-hydroxyandrost-5-en-17-one ethylcarbamate in106 ml. of tetrahydrofuran was added 106 ml. of ethanol followed by 1.06

.g. (0.28 mole) of sodium borohydride. The reaction was stirred at roomtemperature for 90 min. and poured into 2 l. of ice and water. Theresulting precipitate was collected by filtration and dissolved indichloromethane. The solution was washed with water, dried andevaporated to give a colorless crystalline residue. This wasrecrystallized from dichloromethane-ethyl acetate to' giveandrost-S-ene- 3B-17B-diol S-ethylcarbamate; M.P. 201-202" C.

EXAMPLE 20 Androst-5-ene-3fl,17/3-diol 3-ethylcarbamate 17-acetate Asolution of 3.00 g. (0.0083 mole) of androst-S-ene- 3 3,17;8-diol3-ethylcarbamate in 15 ml. of pyridine and EXAMPLE 214,6-dichloro-17a-hydroxypregna-4,6-diene-3,20-dione acetate To a coldsolution of 1.0160 g. of 6-Ch1OIO-17ozhydroxypregna-4,6-dien-3,20-dioneacetate in 10 ml. of alcohol-free chloroform was rapidly added (at 0)3.4 ml. of a 0.817 M solution of C1 in dry carbon tetrachloride. Thissolution was stored at 0 for 18 hrs. The solvent was then removed underreduced pressure and the residue was treated with 25 ml. of heptane andthe solvent was again removed under reduced pressure. This operation wasrepeated a second time. The residue was then treated with 4 ml. of drypyridine and the resulting solution was heated on a steam bath for 5minutes. The solution was then allowed to stand at room temperatureovernight (pyridine hydrochloride precipitated from the reactionmixture). To the pyridine solution was then added 50 ml. of chloroformand the resulting solution was twice extracted, each time with 50 ml. of1 N hydrochloric acid. The aqueous layer was then extracted with 25 ml.of ether. The organic layers were combined, dried over magnesium sulfateand evaporated under reduced pressure. The residue was treated with 25ml. of heptane which was evaporated under reduced pressure. Thisoperation was repeated a second time giving crude4,6-dichloro-l7a-hydroxypregna-4,6-diene-3,20-dione acetate which wasrecrystallized twice from dichloromethaneethyl acetate yieldingcrystals; M.P. 241243.

EXAMPLE 22 4,6-dichloro-3B,l7a-dihydroxypregna-4,6-dien-20-one17-acetate A solution of 2.000 g. of4,6-dichloro-3B,17a-hydroxypregna4,6-diene-3,20-dione acetate in 20 ml.of anhydrous tetrahydrofuran was added dropwise over a 15 minute periodto 3.280 g. of lithium tri-t-butoxyaluminum hydride in 20 ml. ofanhydrous tetrahydrofuran under a nitrogen atmosphere. After stirring atroom temperature for 2 hours, 20 ml. of acetone was added followed by150 ml. of 10% acetic acid in water. The mixture was extracted with two75 ml. portions of chloroform, the organic layers were combined, washedvwith 5% sodium 14 bicarbonate, dried with magnesium sulfate andconcentrated under reduced pressure. The crude solid was crystallizedfrom acetone-hexane which upon recrystallization from thersame solventsystem yielded 4,6-dichloro-3,8,l7adihydroxypregna-4,6-dien-20-one17-acetate; M.P. 255 257.

EXAMPLE 23 4,6--dichloro-17a-hydroxy-16-methylenepregna-4,6diene-3,20-dione acetate To a solution of 3.9 g. of6-chloro-17a-hydr0xy-16- methylenepregna-4,6-diene-3,20-dione acetate in25 ml. of alcohol-free chloroform was added dropwise (at 0) 11.3 ml. (5%excess) of a 0.87 molar solution of chlorine in carbon tetrachloride.The resultant solution was stirred for one hour at 0 and the solventswere then removed under reduced pressure. The resulting foam was treatedwith 10 ml. of dry pyridine and then stirred at room temperature for 2hours. Diethyl ether (200 ml.) was added and the mixture was twiceextracted, each time with ml. of 1 N hydrochloric acid. The diethylether solution was then dried and the solvent was removed under reducedpressure. The residue was triturated with diethyl ether to give amaterial which was chromatographed on silica gel. Elution with 2% ethylacetate-benzene gave20:,4,6-trichloro-17a-hydroxy-16-methylenepregna-4,6-diene-3,20-dioneacetate which upon crystallization from dichloromethane/diethyl ethermelted at 235-238 d. (dec. begins 225).

Further elution with 5% ethyl acetate-benzene gave 4,6-d1Chl01'0-17oc-hYdTOXY 16 methylenepregna 4,6 diene- 3,20-dione acetatewhich upon crystallization from dichloromethane-diethyl ether melted at218-219".

EXAMPLE 24 4,6-dichloro-3fl,17a-dihydroxy-16-methylenepregna-4,6-dien-20-one l7-acetate To a solution of 0.5 g. of4,6-dichloro-17u-hydroxy-16- methylenepregna-4,6-diene-3,ZO-dioneacetate in 10 ml. of dry tetrahydrofuran was added dropwise a solutionof 1.3 g. of lithium tri-t-butoxyaluminum hydride in 10 m1. of drytetrahydrofuran. After stirring for 2 hours at room temperature thesolution was cooled in an ice bath and 1.0 ml. of acetone was added.After 15 minutes the solution was poured into 150 ml. of chloroform andthe chloro- Tablets of the following formulation were prepared asdescribed below:

Mg. per tablet 3p,17a-dihydroxypregn-4-en 20 one 3-carbamate 17-acetate2.55 Dicalcium phosphate, unmilled 232.45 Corn starch 12.50 Magnesiumstearate 2.50

Total weight 250.00

The 373,17a-dihydroxypregn-4-en 20 one 3-carbamate 17-acetate and cornstarch were blended in a suitable size mixer. The mix was then blendedwith an equal quantity of dicalcium phosphate. The mixture was blendedfor five minutes with the balance of the dicalcium phosphate andmagnesium stearate. The mixture was then compressed.

1 EXAMPLE 26 Suppositories of the following formulation were prepared asdescribed below:

Mg. per 1.3 gm. suppository 33,l7wdihydroxypregn-4-en 20 one 3-carbamate17-acetate 0.005 Wecobee M 1 1.250 Carnauba Wax 0.045

EXAMPLE 27 Capsules of the following formulation were prepared asfollows:

Mg. per capsule 313,17u-dihydroxypregn-4-en-20-one 3-ca-rbamate 17-acetate 5 Lactose 178 Corn starch 37 Talc 5 Total weight3B,l7u-dihydroxypregn-4-en 20 one 3-carbarnate l7- acetate was mixedwith the lactose and corn starch in a suitable mixer. The mixture wasfurther blended by passing through a Fitzpatrick comminuting machinewith a #1A screen with knives forward. The blended powder was returnedto the mixer, the talc added and blended thoroughly. The mixture wasthen filled into #4 hard shell gelatin capsules on a Parke Daviscapsulating machine.

EXAMPLE 28 A 0.1% cream of the following formulation was prepared asfollows:

Mg. per gram 3p,l7a-dihydroxypregni-en-20-one 3 carbamate 17-acetate1.00 Stearyl alcohol 100.00

Cetyl alcohol 15.00 White petrolatum 70.00 Methyl parahydroxybenzoate,U.S.P. 2.00 Propyl parahydroxybenzoate, U.S.P. 0.50 Isopropyl palmitate60.00 Polyoxyl 40 stearate, U.S.P. 40.00 Propylene glycol 120.00Disodium versenate 0.10 Distilled water 597.16

The stearyl alcohol, cetyl alcohol, petrolatum, propylparahydroxybenzoate, isopropyl palmitate and polyoxyl 40 stearate weremelted at 75 C. The mixture was cooled to and maintained at 70 C.Disodium versenate and methyl parahydroxybenzoate were dissolved in hotdistilled water to which was added the propylene glycol. The solutionwas mixed at 75 C. and slowly added to the oil solution preparedpreviously, using slow agitation. The emulsion was gradually cooled withslow stirring. When the temperature of the ointment reached C., 33,17a-dihydroxypregn-4-en-20-one 3-carbamate 17 acetate was added andmixed with the ointment. When the temperature of the ointment reached 50C., cold water was circulated in the jacket of the kettle and theointment was cooled to 30 C. with stirring. The ointment was thentransferred to storage containers.

16 EXAMPLE :9

A tablet of the following formulation was prepared as described inExample 25:

Mg. per tablet 6-chloro-3fl,la-dihydroxyprepgna-4,6 diene 20- one3-dimethylcarbamate 17-acetate' 2.55 'Dicalcium phosphate, unmilled232.45 Corn starch 12.50 Magnesium stearate 2.50

Total weight 2.50.00

EXAMPLE 30 A suppository of the following formulation was prepared asdescribed in Example 26:

Gm. per 1.3 gm.

suppository G-chloro-Sfi,l7m-dihydroxypregna-4,6-dien-20 one3-dimethylcarbamate l7-acetate 0.005 Wecobee M 1.250 Carnauba wax 0.045

EXAMPLE 31 A capsule of the following formulation was prepared asdescribed in Example 27:

' 7 Mg. per capsule 6chloro-3fl,l7a-dihydroxypregna-4,6-dien-20-one 3-dimethylcarbamate 17-acetate 5 Lactose 178 Cornstarch 37 Talc 5 Totalweight 225 EXAMPLE 32 A 0.1% cream of the following formulation wasprepared as described in Example 28:

Mg. per gram fi-chloro-3 8,17a-dihydroxypregna-4,6 dien 20- EXAM PLE 33A tablet of the following formulation was prepared as described inExample 25:

Mg. per tablet l7u-methylandrost-5-ene-3p,17,8-diol bis carbamate 2.55Dicalcium phosphate, unmilled 232.45 Corn starch 12.50 Magnesiumstearate 2.50

Total weight 250.00

EXAMPLE 34 A suppository of the following formulation was prepared asdescribed in Example 26:

Gm. per 1.3 gm. suppository l7a-methylandrost-5 ene-3[3,1713 diol biscarbamate 0.005 Wecobee M 1.250 Carnauba wax 0.045

17 EXAMPLE 3s A capsule of the following formulation was prepared asdescribed in Example 27:

Mg. per capsule l7a-methylandrost-5-ene-3,8,17B-diol bis-carbamate 5Lactose 178 Corn starch 37 Talc 5 Total weight 225 EXAMPLE 36 A 0.1%cream of the following formulation was prepared as described in Example28:

Mg. per gram 17a-methylandrost-5-ene-3fi,17fi-diol bis carba- 1. Acompound selected from the group consisting of compounds of theformulas:

and

wherein R is X and X are halogen or hydrogen; R and R are hydrogen,lower alkyl, lower alkenyl or aryl; R is hydrogen, lower alkyl or loweralkylidene; R is individually hydrogen, lower alkyl, hydroxy or loweralkanoyloxy; R is individlually hydroxy, acetyl, lower alkanoyloxy or oO NH2i and the dotted bond is a single bond or a double bond betweencarbon atoms in the 6 and 7 position; with the proviso that when R is 18hydroxy or lower alkanoyloxy, R is hydrogen or lower alkyl and wherein Ris acetyl, R is hydroxy or lower alkanoyloxy; and with the furtherproviso that when X and X are hydrogen, the dotted bond is a singlebond.

2. The compound of claim 1 having the formula:

aha o O R-iL-O wherein R R and R are as above. I

3. The compound of claim 2 wherein said compound is3B,17wdihydroxypregn-4-en-20-one 3-carbamate.

. 4. The compound of claim 1 having the formula:

wherein X R, R and R are as above.

5. The compound of claim 4 wherein said compound is6-chloro-3B,17a-dihydroxypregna-4,6-dien 20 one 3- carbamate 17-acetate.

6. The compound of claim 1 having the formula:

wherein R, R and R are as above; R' is hydroxy or lower alkanoyloxy or Rand R' taken together form an oxo group.

7. The compound of claim 6 wherein said compound is17oc-methylandrost-4-ene-3B,17p-diol 3-ethylcarbamate. 8. The compoundof claim 1 having the formula:

.itol

wherein R and R are as above and R' is individually hydroxy or loweralkanoyloxy or R and R' taken together form an oxo group.

9. The compound of claim 8 wherein said compound is17a-methylandrost-5-ene-3,9,17fl-diol 3 phenylcarbamate.

19 10. A process for obtaining a compound selected from the groupconsisting of compounds of the formulas:

wherein R is RI X and X are halogen or hydrogen; R and R are hydrogen,lower alkyl, lower alkenyl or aryl; R is hydrogen, lower alkyl or loweralkylidene; R is individually hydrogen, lower alkyl, hydroxy orlower'alkanoyloxy; R is individually hydroxy, acetyl or loweralkanoyloxy or O O--JJJNH: or R and R taken together form an oxo group;and the dotted bond is a single bond or a double bond between carbonatoms in the 6 or 7 position; with the proviso that when R is -O -NH2hydroxy or lower alkanoyloxy, R is hydrogen or lower alkyl and when R isacetyl, R is hydroxy or lower alkanoyloxy; and with the further provisothat when X and X are hydrogen, the dotted bond is a single bond;

comprising reacting a compound selected from the group consisting ofcompounds of the formulas:

wherein X X R R R and the dotted bond are as above;

with an amine compound of the formula:

wherein R and R are as above.

11; The process of claim wherein an excess of the amine compound isutilized as the solvent for the process.

12. A process for obtaining a compound selected from the groupconsisting of compounds of the formulas:

and

wherein R is X and X are halogen or hydrogen; R is hydrogen;

R is lower alkyl, lower alkenyl or aryl; R is hydrogen, lower alkyl orlower alkylidene; R is individually hydrogen, lower alkyl, hydroxy orlower alkanoyloxy; R is individually hydroxy, or lower alkenoyloxy; R isindividually hydroxy, acetyl, lower alkanoyloxy or o 0- NHz or R and Rtaken together from an oxo group; and the dotted bond is a single bondor a double bond between carbon atoms in the 6 or 7 position; with theproviso that when R is 0 O-ANH2, hydroxy or lower alkanoyloxy, R ishydrogen or lower alkyl and when R is acetyl, R is hydroxy or loweralkanoyloxy; and with the further proviso that when X; and X arehydrogen, the dotted bond is a single bond; 1

comprising reacting a compond selected from the group consisting ofcompounds of the formulas:

and

wherein X X R R R and the dotted bond are as above;

with a compond of the formula:

RF wherein R is as above.

i 13. 'Ihe process of claim 12 wherein said process is carried out inthe presence of an organic amine base.

14. The process of claim 13 wherein mid organic amine base is selectedfrom the group consisting oi pyridine, triethylamine and collidine.

15. A process for obtaining a compound selected from the groupconsisting of compounds of the formulas:

TMRI

wherein X and X; are halogen or hydrogen; R is hydrogen, lower alkyl orlower alkylidene; R is individually hydrogen, lower alkyl, hydroxy orlower alkanoyloxy; R is individually hydroxy, acetyl, lower alkanoyloxyor -0PJNH:

or R and R taken together form an axe group; and the dotted bond is asingle bond or a double bond between carbon atoms in the 6 or 7position; with the proviso that when R is 0 O--ii-NH: hydroxy or loweralkanoyloxy, R is hydrogen or lower alkyl and when R is acetyl, R ishydroxy or lower alkanoyloxy; and with the further proviso that when Xand X; are hydrogen, and dotted bond is a single bond;

comprising reacting a compound selected from the group consisting ofcompounds of the formulas:

HO and if X:

wherein X X R R R and the dotted bond are as above;

with phenyl chloroformate.

16. The process of claim wherein said process is carried out in thepresence of an organic amine base.

17. The process of claim 16 wherein said organic amine base is selectedfrom the group consisting of pyridine, triethylamine and collidine.

18. A process for obtaining a compound selected from the groupconsisting of compounds of the formulas:

and

f at, h

wherein X and X are halogen or hydrogen; R and R are hydrogen, loweralkyl, lower alkenyl or aryl; R is hydrogen, lower alkyl or loweralkylidene; R is individually hydrogen, lower alkyl, hydroxy or loweralkanoyloxy; R is individually hydroxy, acetyl, lower alkanoyloxy or orR and R taken together form an oxo group; and the dotted bond is asingle bond or a double bond between carbon atoms in the 6 and 7position; with the proviso that when R is hydroxy or lower alkanoyloxy,R is hydrogen or lower alkyl and when R is acetyl, R is hydroxy or loweralkanoyloxy; and with the further proviso that when X and X, arehydrogen, the dotted bond is a single bond;

comprising reacting a compound selected from the group consisting ofcompounds of the formulas:

and R5 R X] XI wherein R is hydroxy or o R, -O N 1, 2, R1, R R R R andthe dotted bond are as above; and at least one of R and R is hydroxy;

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 787 u3 Dated Januar-v '22 197 4 I v Kenneth Earl Fahrenholtz It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby correctedas shown below:

Column 1 Formula II DRM PO-IOSO (10-69) page UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No. '3 1787 1 5 Dated January 22. 1 7"lnventofls) Kenneth Earl Fahrenholtz It is certified that error appearsin the above-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 2 Formula la should be )RM P04 050 (10-69) USCOMM-DC 60376-P69us. covnnucu'r PRINTING ornc: 1 is" 0-366-334.

. Q UNITED STATES PATENT OFFICE page CERTIFICATE OF CORRECTION Patent787 J53 Dated .Tqnu'zry l? IQZLI Inventor s Kenneth Earl Fahrenholtz Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 3 Formula II a should be uscoMM-Dc wan-P09 )RM FWD-1050 (10-69) hu.s covzuknzur mu'rms OFFICE m9 o-us-su.

UNITED STATES PATENT OFFICE 3 0 CERTIFICATE OF CORRECTION Patent 2,787452 Dated Januarv ?2 l Y Inventor(s) Kenneth Earl Fahrenholtz It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

The first formula in Claim l 'should be FORM PO-IOSO (10-69) uscoMM-Dcwan-P69 [1.3 GOVERNMENT FI'UN ING OFFICE I I9, 36$-33l.

UNITED STATES PATENT OFFICE g 5 CERTIFICATE OF CORRECTION Patent No. '2I n Dated Janua v p2 107 4 Inventor(s) Kenneth Earl Fahrenholtz It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 19 second part of first formula in Claim 10 should be FORMPO-IOSO (10-59) USCOMM-DC 60376-P69 w v.5, covsnunzu'r rnm'rmc OFFICElsu o-ass-au.

- UNITED STATES PATENT OFFICE p 6 CERTIFICATE OF CORRECTION Patent No. 38 34 Dated January 22, 197 4 Inventor(s) Kenneth Earl Fahrenholtz It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 20 first part of second formula in Claim 12 H k l I 7 should beSigned and sealed this 6th day of August 197A.

(SEAL) Attest:

MCCOY GIBSON, JR. C. MARSHALL DANN Attescing Officer Commissioner ofPatents

